Orphan nuclear receptor estrogen-related receptor-beta suppresses in vitro and in vivo growth of prostate cancer cells via p21(WAF1/CIP1) induction and as a potential therapeutic target in prostate cancer

Abstract

Recent studies indicate that estrogen-related receptors (ERRs) are involved in similar estrogen receptor (ER) regulatory pathways and play roles in energy and lipid metabolism. Here, we analysed the functional role of ERRbeta in prostate cancer cell growth regulation in an androgen-sensitive and androgen-insensitive prostate cancer cell lines. ERRbeta was expressed in normal human prostates, but exhibited a reduced expression in prostate cancer lesions. Stable ERRbeta expression suppressed significantly cell proliferation and tumorigenicity of LNCaP and DU145 cells, accompanied by an S-phase suppression and increased p21 expression. Reporter and chromatin immunoprecipitation assays showed that ERRbeta could directly transactivate p21 gene promoter, which could be further enhanced by peroxisome proliferator-activated receptor-gamma coactivator-1alpha. Truncation analysis showed that ERRbeta-mediated p21 transactivation and prostate cancer cell growth inhibition required intact DNA-binding domain and AF2 domains in ERRbeta. Interestingly, ERRbeta displayed a cell cycle associated downregulated expression pattern in ERRbeta-transduced and non-transduced cells. Finally, we showed that ERRbeta-mediated growth inhibition could be potentiated by an ERRbeta/gamma agonist DY131. Knockdown of ERRbeta by RNA interference could reduce the DY131-induced growth inhibition in prostate cancer cells. Taken together, our findings indicate that ERRbeta performs a tumor suppressing function in prostate cancer cells, and targeting ERRbeta could be a potential therapeutic strategy for prostate cancer.